The Role of BiP Nucleotide Exchange Factor Sil1 in Immunoglobulin Biosynthesis
type: CreativeWork
description: BiP is an essential endoplasmic reticulum resident molecular chaperone of the HSP70 family that binds exposed hydrophobic regions of unfolded proteins. Substrates bound by BiP are protected from dangerous non-specific interaction with other unfolded proteins via their aggregation prone exposed hydrophobic regions, which are normally buried in the native state, and act as BiP binding targets. For these substrates to mature into the native state, BiP must be released. Like all HSP70 family members, cycles of BiP binding and release are nucleotide dependent and facilitated by two genres of cochaperones, HSP40s, and nucleotide exchange factors (NEFs). HSP40s function in stimulating the hydrolysis of ATP, which causes a conformational change that induces tight binding of BiP to substrate, whereas, NEFs stimulate the escape of ADP that allows BiP to release substrate so that it can progress toward its final native state. In 2002, we identified a mammalian BiP associated protein, Sil1, with nucleotide exchange activity. In 2005, Sil1 became the first molecular cochaperone known to cause disease upon discovery of mutations that lead to Marinesco-Sjögren Syndrome (MSS), a debilitating recessive disease characterized by severe cerebellar atrophy and a wide range of systemic defects. Now, many Sil1 mutations in MSS are known to result in interrupted BiP binding or Sil1 instability. We have attained an animal model of MSS with a Sil1 mutation that results in loss of a major BiP interaction site. This model, known as the Woozy mouse due to its striking ataxic phenotype, closely phenocopies many aspects of human MSS yet has been the spotlight of very few studies. For the first time, we have performed a detailed examination on the effects of Sil1 loss on a specific BiP substrate, immunoglobulin (Ig) heavy chain. This is a highly relevant target to study for two main reasons. First, because Ig is the best characterized BiP substrate and is readily tractable by several well-establis…
abstract: BiP is an essential endoplasmic reticulum resident molecular chaperone of the HSP70 family that binds exposed hydrophobic regions of unfolded proteins. Substrates bound by BiP are protected from dangerous non-specific interaction with other unfolded proteins via their aggregation prone exposed hydrophobic regions, which are normally buried in the native state, and act as BiP binding targets. For these substrates to mature into the native state, BiP must be released. Like all HSP70 family members, cycles of BiP binding and release are nucleotide dependent and facilitated by two genres of cochaperones, HSP40s, and nucleotide exchange factors (NEFs). HSP40s function in stimulating the hydrolysis of ATP, which causes a conformational change that induces tight binding of BiP to substrate, whereas, NEFs stimulate the escape of ADP that allows BiP to release substrate so that it can progress toward its final native state. In 2002, we identified a mammalian BiP associated protein, Sil1, with nucleotide exchange activity. In 2005, Sil1 became the first molecular cochaperone known to cause disease upon discovery of mutations that lead to Marinesco-Sjögren Syndrome (MSS), a debilitating recessive disease characterized by severe cerebellar atrophy and a wide range of systemic defects. Now, many Sil1 mutations in MSS are known to result in interrupted BiP binding or Sil1 instability. We have attained an animal model of MSS with a Sil1 mutation that results in loss of a major BiP interaction site. This model, known as the Woozy mouse due to its striking ataxic phenotype, closely phenocopies many aspects of human MSS yet has been the spotlight of very few studies. For the first time, we have performed a detailed examination on the effects of Sil1 loss on a specific BiP substrate, immunoglobulin (Ig) heavy chain. This is a highly relevant target to study for two main reasons. First, because Ig is the best characterized BiP substrate and is readily tractable by several well-establis…
author: Sanford, Tyler
keywords: BiP, Sil1, Grp170, MSS, Marinesco-Sjögren Syndrome, Nucleotide exchage factor, Medical Cell Biology, Medical Immunology, Medical Sciences, Medicine and Health Sciences
date published: 2012-12-01T08:00:00Z
date modified: 2026-07-24T05:00:17Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center